N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

Abstract

Difluorocyclopropanation of N‐vinylazoles with the CF3SiMe3–NaI system was studied. It was found that N‐vinylpyrazoles could be transformed into the corresponding N‐difluorocyclopropyl‐substituted derivatives. The method was efficient on a 100 g scale and could be applied for the preparation of various functionalized regioisomeric pyrazole derivatives bearing a gem‐difluorocyclopropane moiety, such as amines, carboxylic acids, aldehydes, bromides, and boronic esters. It was found that N‐difluorocyclopropylpyrazole moiety tolerated many common reagents including nitrating mixture, bromine, aqueous acids and alkali, KMnO4, LiBH4, and Pd0 complexes; it was unstable towards AlCl3, catalytic hydrogenation and lithiation conditions. The products obtained are advanced building blocks which of potential importance to medicinal and agrochemistry.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…In the last decade, a significant attention was paid to the difluorocyclopropanation of functionalized alkenes with the CF 3 SiMe 3 -NaI system originally introduced by Prakash, Hu, and co-workers. [496] This reagent system was applied successfully to the alkenes bearing a protected secondary amino, [497] pyrazole, [498,499] trifluoroborate, [500] protected hydroxyl, and other functional groups [501] (Scheme 64). In some of the aforementioned cases, a modification of the original method proposed by our group, "slow addition protocol", was required.…”

A mechanistic investigation of the Pd-catalyzed cross-coupling betweenN-tosylhydrazones and aryl halides

“…4.2 Anion-catalyzed reactions with TMSCF 3 with a) carbonyls, 104,199,200 and b) alkenes. 105,[201][202][203][204][205]…”

Revisiting the Chemistry of Vinylpyrazoles: Properties, Synthesis, and Reactivity

“…N -vinylpyrazoles 43 and 45 undergo difluorocyclopropanation with CF 3 SiMe 3 -NaI system with formation of the corresponding N -difluorocyclopropyl derivatives 44 and 46 in very good yield ( Scheme 16 ). These compounds are stable and undergo further regioselective functionalization to afford gem -difluorocyclopropylpyrazole amines, carboxylic acids, aldehydes, bromides, and boronic derivatives [ 64 ]. It is noteworthy that this method is not successful for the preparation of other azole derivatives, such as imidazoles, triazoles, and tetrazoles, possibly because of the presence of a nucleophilic nitrogen atom (in the case of the imidazole) or electronic effects for the other representatives.…”